1. Field of the Invention
The invention relates to novel substances and compounds which are capable of concertedly inhibiting the enzymes dipeptidyl peptidase IV (DPIV) as well as peptidases having an analogous enzymatic effect and alanyl aminopeptidase N (APN) as well as peptidases having an analogous enzymatic effect (“dual inhibitors”). Furthermore, the invention relates to processes to prepare the novel dual inhibitors of DPIV and APN. The invention also relates to the afore-mentioned novel compounds for a use in the medical field. Moreover, the invention relates to a use of the afore-mentioned dual inhibitors for a prophylaxis and a therapy of diseases showing an excessive immune response and having an inflammatory genesis, of neuronal diseases and of cerebral damage, of tumor diseases, of skin diseases, of diabetes of the type II and of SARS.
2. Description of the Prior Art
The enzyme dipeptidyl peptidase IV (DPIV, CD26, EC 3.4.14.5) is a serine protease existing ubiquituously and catalyzing the hydrolysis of peptides specifically after proline and—to a lesser extent—after alanine or—with restrictions—after further amino acids like serine, threonine, valine and glycine at the second position of the N-terminus. Enzymes belonging to the gene family of enzymes having DPIV-analogous enzymatic effect are—inter alia—DP 8, DP 9 and FAP/seprase [T. Chen et al.: Adv. Exp. Med. Biol. 524, 79, 2003]. A substrate specifity analogous to DPIV was also found for attractin (mahagony protein) [J. S. Duke-Cohan et al.: J. Immunol. 156, 1714, 1996]. Said enzyme is also inhibited by DPIV inhibitors.
Belonging to the group of alanyl aminopeptidases (also existing ubiquituously) are the aminopeptidase N (APN, CD13, EC 3.4.11.2) predominantly appearing as a membrane protein of the type II, as well as the cytosolic soluble alanyl aminopeptidase (EC 3.4.11.14, puromycine-sensitive aminopeptidase, amino-peptidase PS, encephaline-degrading aminopeptidase). Alanyl aminopeptidases (including the afore-mentioned aminopeptidases) act in dependency of a metal, for example in dependency of zinc, and catalyze the hydrolysis of peptide bonds after the N-terminal amino acids of oligopeptides, in the case of APN with a preference of alanine at the N-terminus [A. J. Barrett et al.: Handbook of Proteo-lytic Enzymes, Academic Press 1998]. All inhibitors of aminopeptidase N also inhibit the cytosolic alanyl aminopeptidase, while specific inhibitors of the cytosolic aminopeptidase exist [M. Komodo et al.: Bioorg. and Med. Chem. 9, 121, 2001].
For both groups of enzymes, important biologic functions were proved in different cell systems. This is true—inter alia—for the immune system [U. Lendeckel et al.: Intern. J. Mol. Med. 4, 17, 1999; T. Kähne et al.: Intern. J. Mol. Med. 4, 3, 1999; I. De Meester et al.: Advanc. Exp. Med. Biol. 524, 3, 2002; International Patent Application No. WO 01/89,569; International Patent Application No. WO 02/053,170; International Patent Application No. PCT/EP 03/07,199]; the neuronal system [International Patent Application No. WO 02/053,169 and German Patent Application No. 103 37 074.9]; the fibroblasts [German Patent Application No. 103 30 842.3]; the keratinocytes [International Patent Application No. WO 02/053,170]; the sebaceous gland cells/sebatocytes [International Patent Application No. PCT/EP 03/02,356]; tumors as well as for virus-caused infections as, for example coronavirusses [D. P. Kontoyiannis et al.: Lancet 361, 1558, 2003].
The capability, of DPIV, of specifically inactivating the incretory hormones GIP and GLP led to the development of a new therapeutic concept for treating glucose metabolic disorders [D. M. Evans: Drugs 5, 577, 2002].
For both groups of enzymes, there are known different inhibitors [reviews are found in: D. M. Evans: Drugs 5, 577, 2002; and: M.-C. Fournie-Zaluski and B. P. Roques: in J. Langner and S. Ansorge: Ectopeptidases, Kluwer Academic/Plenum Publishers, p. 51, 2002].
The isolated inhibition of the alanyl aminopeptidases and of the dipeptidyl peptidase IV as well as the inhibition of enzymes having an analogous substrate specificity, in particular the combined inhibition of enzymes of both groups of enzymes, results into a strong inhibition of the DNA synthesis of immune cells and, hence, into a strong inhibition of the cell propagation as well as into a change of the cytokine production, particularly into an induction of the (immune-regulatory effective) TGF-β1 [International Patent Application No. WO 01/89,569; International Patent Application No. WO 02/053,170] as well as into an inhibition of the generation and release of inflammatory cytokines of the type TH1 and TH2, e.g. interleukine-4 (IL-4) [International Patent Application No. WO 02/053,170 and German Patent Application No. 101 02 392.8]. Inhibitors of alanyl aminopeptidase effect a strong induction of TGF-β1 at regulatory T-cells [International Patent Application No. PCT/EP 03/07,199]. In the neuronal system, a decrease or retardation of acute and chronic cerebral damage processes was proved by an inhibition of both enzyme systems [International Patent Application No. WO 02/053,169 and German Patent Application No. 103 37 074.9]. Moreover, it was proved for fibroblasts [German Patent Application No. 103 30 842.3], keratinocytes [International Patent Application No. WO 02/053,170) and sebatocytes [International Patent Application No. PCT/EP 03/02,356] that the combined inhibition of alanyl aminopeptidase N and DPIV effects an inhibition of the growth and a change of the cytokine production.
This results into the surprising fact that the alanyl aminopeptidases and the dipeptidyl peptidase IV as well as enzymes having an analogous effect perform fundamental central biologic functions in different organs and cell systems, and that a combined inhibition of both groups of enzymes represents a new effective therapeutic principle for the treatment of various—im most cases chronic—diseases.
In accepted animal models, the applicants could show in the meantime that, in particular, the combined administration of inhibitors on both groups of said peptidases results into an inhibition of the growth of different cell systems and into a suppression of an excessive immune response, of chronic inflammatory processes and of cerebral damages, also in vivo [International Patent Application No. WO 01/89,569]. The isolated administration of single known inhibitors results into a diminished effect.
The results reported up to now were obtained predominantly by means of known inhibitors of alanyl aminopeptidase N and dipeptidyl peptidase IV alone, being described in the literature and being—in part—commercially available but in particular by combinations of inhibitors of enzymes of both groups.